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Molecular signature of response and potential pathways related to resistance to the HSP90 inhibitor, 17AAG, in breast cancer.

Zajac M, Gomez G, Benitez J, Martínez-Delgado B - BMC Med Genomics (2010)

Bottom Line: In addition, different patterns of HSP90 client transcriptional changes after 17AAG were identified associated to the sensitive cell lines, which could be useful to evaluate drug effectiveness.Finally, we have found differentially expressed pathways associated to resistance to 17AAG.Our study shows that global mRNA expression analysis is a useful strategy to examine molecular effects of drugs, which allowed us the discovery of new biomarkers of 17AAG activity and provided more insights into the complex mechanism of 17AAG resistance.

View Article: PubMed Central - HTML - PubMed

Affiliation: Human Genetics Group, Spanish National Cancer Centre, Madrid, Spain.

ABSTRACT

Background: HSP90 may be a favorable target for investigational therapy in breast cancer. In fact, the HSP90 inhibitor, 17AAG, currently has entered in phase II clinical trials as an anticancer agent in breast and other tumors. Since HSP90 inhibition leads to global depletion of oncogenic proteins involved in multiple pathways we applied global analysis using gene array technology to study new genes and pathways involved in the drug response in breast cancer.

Methods: Gene expression profiling using Whole Human Genome Agilent array technology was applied to a total of six sensitive and two resistant breast cancer cell lines pre-treatment and treated with the 17AAG for 24 and 48 hours.

Results: We have identified a common molecular signature of response to 17AAG composed of 35 genes which include novel pharmacodynamic markers of this drug. In addition, different patterns of HSP90 client transcriptional changes after 17AAG were identified associated to the sensitive cell lines, which could be useful to evaluate drug effectiveness. Finally, we have found differentially expressed pathways associated to resistance to 17AAG. We observed significant activation of NF-κB and MAPK pathways in resistant cells upon treatment, indicating that these pathways could be potentially targeted to overcome resistance.

Conclusions: Our study shows that global mRNA expression analysis is a useful strategy to examine molecular effects of drugs, which allowed us the discovery of new biomarkers of 17AAG activity and provided more insights into the complex mechanism of 17AAG resistance.

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Related in: MedlinePlus

Transcriptional changes of HSP90 clients. A) Heatmap representing the differences in the mRNA expression found in the list of known HSP90 clients and interactors in treated breast cancer cell lines (increments over untreated cells in red, reductions in blue). Weaker variations in resistant cell lines are shown. B) Significant HSP90 client transcriptional changes in individual cell lines following 17AAG treatment. Genes for which mRNAs exhibited over 2-fold increase or reduction are shown for the different cell lines. Stars indicate genes commonly changing at least in four of the six cell lines.
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Figure 4: Transcriptional changes of HSP90 clients. A) Heatmap representing the differences in the mRNA expression found in the list of known HSP90 clients and interactors in treated breast cancer cell lines (increments over untreated cells in red, reductions in blue). Weaker variations in resistant cell lines are shown. B) Significant HSP90 client transcriptional changes in individual cell lines following 17AAG treatment. Genes for which mRNAs exhibited over 2-fold increase or reduction are shown for the different cell lines. Stars indicate genes commonly changing at least in four of the six cell lines.

Mentions: The cellular response to 17AAG has a complex nature with effects including protein and transcriptional changes [25]. As the treatment with 17AAG has a global effect in the cell through depletion of client proteins, we were interested in analysing the subsequent changes induced by HSP90 inhibition at transcription level. We characterized the profile of transcriptional changes of the list of 168 well reported Hsp90 client proteins and interactors available on the Picard lab home page http://www.picard.ch/DP/DPhome.html. Since expression of HSP90 client proteins vary according to cell type, we have presented the data of HSP90 interactors' expression as differences in expression in treated cell lines versus their corresponding untreated cells. This analysis revealed that each cell line has an individual pattern of Hsp90 interactors' changes (Figure 4A). As we expected, variations in the expression levels of genes coding for client proteins were much lower in resistant cell lines comparing to the sensitive ones (Figure 4A), suggesting that transcriptional changes of at least some client proteins could be taken into account to measure drug effectiveness.


Molecular signature of response and potential pathways related to resistance to the HSP90 inhibitor, 17AAG, in breast cancer.

Zajac M, Gomez G, Benitez J, Martínez-Delgado B - BMC Med Genomics (2010)

Transcriptional changes of HSP90 clients. A) Heatmap representing the differences in the mRNA expression found in the list of known HSP90 clients and interactors in treated breast cancer cell lines (increments over untreated cells in red, reductions in blue). Weaker variations in resistant cell lines are shown. B) Significant HSP90 client transcriptional changes in individual cell lines following 17AAG treatment. Genes for which mRNAs exhibited over 2-fold increase or reduction are shown for the different cell lines. Stars indicate genes commonly changing at least in four of the six cell lines.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2959047&req=5

Figure 4: Transcriptional changes of HSP90 clients. A) Heatmap representing the differences in the mRNA expression found in the list of known HSP90 clients and interactors in treated breast cancer cell lines (increments over untreated cells in red, reductions in blue). Weaker variations in resistant cell lines are shown. B) Significant HSP90 client transcriptional changes in individual cell lines following 17AAG treatment. Genes for which mRNAs exhibited over 2-fold increase or reduction are shown for the different cell lines. Stars indicate genes commonly changing at least in four of the six cell lines.
Mentions: The cellular response to 17AAG has a complex nature with effects including protein and transcriptional changes [25]. As the treatment with 17AAG has a global effect in the cell through depletion of client proteins, we were interested in analysing the subsequent changes induced by HSP90 inhibition at transcription level. We characterized the profile of transcriptional changes of the list of 168 well reported Hsp90 client proteins and interactors available on the Picard lab home page http://www.picard.ch/DP/DPhome.html. Since expression of HSP90 client proteins vary according to cell type, we have presented the data of HSP90 interactors' expression as differences in expression in treated cell lines versus their corresponding untreated cells. This analysis revealed that each cell line has an individual pattern of Hsp90 interactors' changes (Figure 4A). As we expected, variations in the expression levels of genes coding for client proteins were much lower in resistant cell lines comparing to the sensitive ones (Figure 4A), suggesting that transcriptional changes of at least some client proteins could be taken into account to measure drug effectiveness.

Bottom Line: In addition, different patterns of HSP90 client transcriptional changes after 17AAG were identified associated to the sensitive cell lines, which could be useful to evaluate drug effectiveness.Finally, we have found differentially expressed pathways associated to resistance to 17AAG.Our study shows that global mRNA expression analysis is a useful strategy to examine molecular effects of drugs, which allowed us the discovery of new biomarkers of 17AAG activity and provided more insights into the complex mechanism of 17AAG resistance.

View Article: PubMed Central - HTML - PubMed

Affiliation: Human Genetics Group, Spanish National Cancer Centre, Madrid, Spain.

ABSTRACT

Background: HSP90 may be a favorable target for investigational therapy in breast cancer. In fact, the HSP90 inhibitor, 17AAG, currently has entered in phase II clinical trials as an anticancer agent in breast and other tumors. Since HSP90 inhibition leads to global depletion of oncogenic proteins involved in multiple pathways we applied global analysis using gene array technology to study new genes and pathways involved in the drug response in breast cancer.

Methods: Gene expression profiling using Whole Human Genome Agilent array technology was applied to a total of six sensitive and two resistant breast cancer cell lines pre-treatment and treated with the 17AAG for 24 and 48 hours.

Results: We have identified a common molecular signature of response to 17AAG composed of 35 genes which include novel pharmacodynamic markers of this drug. In addition, different patterns of HSP90 client transcriptional changes after 17AAG were identified associated to the sensitive cell lines, which could be useful to evaluate drug effectiveness. Finally, we have found differentially expressed pathways associated to resistance to 17AAG. We observed significant activation of NF-κB and MAPK pathways in resistant cells upon treatment, indicating that these pathways could be potentially targeted to overcome resistance.

Conclusions: Our study shows that global mRNA expression analysis is a useful strategy to examine molecular effects of drugs, which allowed us the discovery of new biomarkers of 17AAG activity and provided more insights into the complex mechanism of 17AAG resistance.

Show MeSH
Related in: MedlinePlus